The eosinophil is an effector cell in the pathophysiology of a wide variety of diseases. Eosinophils possess and/or produce toxic basic proteins, e.g., major basic protein (MBP) and eosinophil-cationic protein (ECP), which they are able to deposit on their targets. They also possess and/or produce toxic oxygen metabolites, including H.sub.2 O.sub.2, and hypohalous acids, including hypobromous acid. For example, hypobromous acid is a potent oxidant that is generated by the eosinophil peroxidase (EPO)+H.sub.2 O.sub.2 +Br.sup.-. The ability of the eosinophil to kill targets can be increased by activators produced by other cells, such as T lymphocytes. These other cells can synthesize a series of glycoprotein hormones that regulate eosinophil function, including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3) and IL-5. Information obtained over the past several years has indicated that eosinophils themselves have the ability to produce cytokines, such as GM-CSF, and IL-3. These cytokines can activate the eosinophil itself, in an autocrine fashion.
Eosinophilia is the infiltration of eosinophils into tissues such as blood or lung, and the activation of those eosinophils, which results in the production of eosinophil-derived proteins that in turn mediate pathogenic effects. The infiltration of eosinophils into tissues, and the subsequent degranulation of the eosinophils, is associated with hypersensitivity diseases such as bronchial asthma, chronic eosinophilic pneumonia, vernal conjunctivitis, allergic conjunctivitis, allergic rhinitis, allergic sinusitis, and allergic gastroenteropathy. Examples of other eosinophil-associated diseases include eosinophilic gastroenteritis, atopic dermatitis, bullous pemphigoid, episodic angioedema associated with eosinophilia, and ulcerative colitis. In all of these diseases, evidence exists that the eosinophil plays a significant, if not major role in pathophysiology.
IL-5 is known to play an important role in the regulation of the immune system and is one of several cytokines regulating organ-specific eosinophil infiltration and degranulation during normal host immune finction (Kita et al., J. Immunol., 149, 629 (1992)). Moreover, IL-5, as well as the cytokines IL-3, IFN-.gamma. and GM-CSF, prolong the survival of eosinophils in vitro (Valenus et al., J. Immunol., 145, 2950 (1990)) and augment eosinophil function (Rothenberg et al., J. Clin. Investig., 81, 1986 (1988); Fujisana et al., J. Immunol., 144, 642 (1990); Silberstein et al., J. Immunol., 137, 3929 (1986)). Furthermore, several types of diseases are correlated with IL-5 activity, including parasitic, autoimmune, atopic and malignant diseases.
Ohnishi et al. (Clin. Exp. Immunol., 104, 325 (1996)) disclose that eosinophils in bronchoalveolar lavage (BAL) fluids from some symptomatic asthma patients had enhanced survival that was primarily due to enhanced IL-5 levels. They further disclose that lidocaine, a topical anesthetic which is employed to obtain BAL fluid, was found to inhibit IL-5 mediated eosinophil survival. The treatment of bronchial asthma and other hypersensitivity diseases with topical anesthetics is disclosed in Gleich et at. (U.S. Pat. Nos. 5,510,339 and 5,631,267).
Glucocorticoids are the most useful class of drugs for treating many eosinophil-related disorders. Glucocorticoids, e.g., dexamethasone, methylprednisolone and hydrocortisone produce eosinopenia in normal persons, decrease circulating eosinophils in patients with eosinophilia, and reduce eosinophil influx at inflammatory sites (Butterfield et al., Anti-inflammatory Steroid Action: Basic and Clinical Aspects, Schleimer et al., eds., Academic Press, Inc., (1989) at page 151). The mechanism of these effects is still uncertain.
Recently Wallen et al. (J. Immunol., 147, 3940 (1991)) reported the dose-dependent inhibition of IL-5-mediated eosinophil survival by dexamethasone, methylprednisolone and hydrocortisone. Moreover, they disclosed that dexamethasone produced a dose-dependent increase in the EC.sub.50 for IL-5-mediated viability enhancement. The relative eosinophil viability inhibitory potencies of the glucocorticoids tested correlated with previously described anti-inflammatory potencies and with the affinities of these agents for the glucocorticoid receptor in the following order: dexamethasone&gt;methylprednisolone&gt;hydrocortisone.
For many patients with asthma, glucocorticoids are the principal therapy, and these patients may require chronic high doses of glucocorticoids for months to years. In fact, the disease gradually becomes one of chronic glucocorticoid toxicity, in that the toxicity of these steroids per se can cause severe morbidity and even mortality in the patients. Furthermore, cessation of glucocorticoid therapy leads to withdrawal symptoms, such as malaise and muscle pain. However, presently glucocorticoids are the only effective therapy for severe asthma, and are prescribed long-term despite their toxicity.
A need exists for improved therapeutic methods to treat eosinophil-associated diseases with agents that reduce or inhibit IL-5 activity.